Identifying patient subgroups who benefit most from a treatment: using administrative claims data to uncover treatment heterogeneity

Figures & data

Table 1.  Baseline characteristics for adolescents.

Baseline characteristics	LDX	OROS-MPH	p-value^a
	(n = 6394)	(n = 6320)
Demographics
Age (years) on index date, mean ± SD	14.9 ± 1.4	14.9 ± 1.4	0.3030
Male, n (%)	4440 (69%)	4138 (65%)	< 0.0001*
ADHD medications, n (%)
Amphetamine short-acting	491 (8%)	156 (2%)	<0.0001*
Amphetamine long-acting	2092 (33%)	679 (11%)	<0.0001*
Methylphenidate short-acting	280 (4%)	313 (5%)	0.1253
Methylphenidate long-acting	1041 (16%)	600 (9%)	<0.0001*
Non-stimulant	681 (11%)	428 (7%)	<0.0001*
Any ADHD medication	3589 (56%)	1798 (28%)	<0.0001*
Comorbid conditions,^b n (%)
Any mental health condition	1546 (24%)	1703 (27%)	0.0003*
Asthma	234 (4%)	228 (4%)	0.8753
Neurological disorders	224 (4%)	157 (2%)	0.0008*
Utilization (number of visits), mean ± SD
Inpatient	0.0 ± 0.3	0.0 ± 0.4	0.9074
Outpatient	5.2 ± 5.8	4.9 ± 5.9	<0.0001*
Emergency room	0.2 ± 0.5	0.2 ± 0.5	0.5427
Other medical services	0.4 ± 1.5	0.3 ± 1.4	0.5726
ADHD-related inpatient^c	0.0 ± 0.1	0.0 ± 0.1	0.4713
ADHD-related outpatient^c	1.6 ± 2.6	1.1 ± 1.9	<0.0001*
ADHD-related emergency room^c	0.0 ± 0.1	0.0 ± 0.1	<0.0001*
ADHD-related other medical services^c	0.1 ± 0.5	0.0 ± 0.5	0.0645
ADHD-related psychotherapy^d	0.8 ± 2.4	0.5 ± 1.7	<0.0001*

LDX, lisdexamfetamine dimesylate; OROS-MPH, osmotic-release oral system methylphenidate; SD, standard deviation.

^a p-values were estimated from Chi-square tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.

^b Comorbid conditions included in the study were selected based on a literature review^28–30.

^c Inpatient, outpatient, emergency room, and other medical services were classified based on the places of services. A medical service was considered as ADHD-related if it was associated with an ADHD diagnosis code (ICD-9 code of 314.0x).

^d Psychotherapy visits were defined as visits to a mental health facility or visits associated with psychotherapy CPT codes. To be qualified as ADHD-related, the events need to associate with an ADHD diagnosis code (ICD-9 code of 314.0x)

* p-value significant at α = 0.05.

Figure 1.  Comparison of study outcomes for LDX vs OROS-MPH^†. (a) Overall population^‡; (b) Pre-defined sub-populations.^‡,$. †Study outcomes were measured over the 12-month post-index period. ‡Mean and p-values were estimated using weighted t-tests for continuous variables. Tests adjusted for baseline characteristics by using IPTW. ^$p-values for trends across the pre-defined sub-populations for risk of switching/augmentation and ADHD-related costs were estimated based on generalized linear models with binomial distribution and normal distributions, respectively, adjusting for baseline characteristics using IPTW and index drugs. Both p-values were <0.001. *p-value significant at α=0.05.

Table 2.  Prediction model for switching/augmentation on OROS-MPH.

Baseline characteristics	Odds ratios*
Baseline ADHD medications (Reference = no ADHD medications)
Amphetamine short-acting	1.41
Amphetamine long-acting	1.91
Methylphenidate short-acting	1.75
Methylphenidate long-acting	1.40
Non-stimulant	2.69
Comorbid conditions (Reference = no comorbid conditions)
Any mental health condition	1.09
Asthma	1.28
Neurological disorders	1.25
Baseline utilization (Reference = no baseline utilization)
Number of inpatient visits	1.23
Number of outpatient visits	1.01
Number of other medical service visits	1.03
Number of ADHD-related inpatient visits	1.21
Number of ADHD-related emergency room visits	2.36
Number of ADHD-related psychotherapy visits	1.01
Index Month (Reference = index month not in April–June)
April–June	0.96
Hosmer-Lemeshow statistic of the model	0.2381

OROS-MPH, osmotic-release oral system methylphenidate.

* Odd ratio > 1 indicates the increased probability of experiencing switching/augmentation for each variable compared to the reference category.

Table 3.  Comparison of outcomes for LDX vs OROS-MPH. Observed and predicted risk of switching/augmentation.

Quartiles^a			Observed outcome rates
	Predicted outcome rates on OROS-MPH		LDX weighted rates^b			OROS-MPH weighted rates^b			p-value^b,c	Adjusted p-value^d
	Mean	Min–Max	n	Mean	95% CI	n	Mean	95% CI
Quartile 1	13.2%	(12.5%, 13.6%)	1316	8.1%	(6.6%, 9.7%)	1082	11.3%	(9.3%, 13.3%)	0.0114*	0.0456*
Quartile 2	15.0%	(13.6%, 17.5%)	1339	14.2%	(12.2%, 16.2%)	1030	17.2%	(14.8%, 19.7%)	0.0542	0.0542
Quartile 3	20.8%	(17.5%, 23.9%)	1863	19.6%	(17.8%, 21.4%)	529	27.8%	(19.6%, 36.1%)	0.0263*	0.0526
Quartile 4	33.7%	(23.9%, 98.6%)	1876	35.1%	(32.9%, 37.3%)	519	42.1%	(36.7%, 47.5%)	0.0139*	0.0456*

LDX, lisdexamfetamine dimesylate; OROS-MPH, osmotic-release oral system methylphenidate.

^aPatients in the validation sample were stratified into quartiles based on the predicted risk scores of switching/augmentation on OROS-MPH estimated using the prediction model, which was established using the training sample to predict the risk of switching/augmentation associated with OROS-MPH.

^bp-values and weighted rates with 95% confidence interval for the actual treatment received were evaluated within each quartile, adjusting for baseline characteristics using IPTW.

^cp-value for trend across quartiles was also tested and was < 0.0001, estimated based on generalized linear model with binomial distribution adjusting for baseline characteristics using IPTW and index drug.

^dp-values were adjusted using the Holm method to control the familywise type I error rate.

*p-value significant at α = 0.05.

Table 4.  Comparison of outcomes for LDX vs OROS-MPH. ADHD-related costs.

Quartiles and cost outcomes^a	LDX weighted costs Mean ± SD^b	OROS-MPH weighted costs Mean ± SD^b	p-value^b,c	Adjusted p-value^d
Quartile 1
Pharmacy costs	737.6 ± 702.3	754.4 ± 811.7
Index drug costs	626.3 ± 579.9	635.8 ± 761.0
Medical costs	333.3 ± 1225.8	307.9 ± 871.6
Total costs	1071.0 ± 1480.4	1062.3 ± 1278.5	0.8280	1.0000
Quartile 2
Pharmacy costs	843.9 ± 795.9	876.0 ± 970.4
Index drug costs	686.4 ± 689.8	703.7 ± 888.1
Medical costs	522.4 ± 2590.4	489.5 ± 1844.7
Total costs	1366.3 ± 2756.5	1365.6 ± 2165.9	0.9919	1.0000
Quartile 3
Pharmacy costs	989.9 ± 725.3	1194.9 ± 2276.0
Index drug costs	745.0 ± 615.0	844.9 ± 1920.6
Medical costs	460.2 ± 1930.4	520.0 ± 4879.6
Total costs	1450.2 ± 2083.2	1714.9 ± 5409.9	0.0227*	0.0908
Quartile 4
Pharmacy costs	1281.8 ± 980.5	1356.2 ± 2174.2
Index drug costs	873.1 ± 713.3	842.5 ± 1703.8
Medical costs	773.2 ± 5091.8	1323.5 ± 13,705.8
Total costs	2055.0 ± 5223.3	2679.7 ± 13,962.7	0.0394*	0.1182

LDX, lisdexamfetamine dimesylate; OROS-MPH, osmotic-release oral system methylphenidate.

^aStudy outcomes were measured over the 12-month post-index period.

^bMean, standard deviation (SD), and p-values were estimated using weighted t-tests within each quartile, adjusting for baseline characteristics using IPTW.

^cp-value for trend across quartiles was also tested and was <0.001, estimated based on a generalized linear model with normal distribution adjusting for baseline characteristics using IPTW and index drugs.

^dp-values were adjusted using the Holm method to control the familywise type I error rate.

*p-value significant at α = 0.05.

Figure 2.  Outcomes achievable with individualized treatment with LDX and OROS-MPH. LDX, lisdexamfetamine dimesylate; OROS-MPH, osmotic-release oral system methylphenidate; ADHD, attention deficit hyperactivity disorder. The squares connected by the dashed black line illustrate different ways of allocating patients based on the stratified medicine approach; black diamond illustrates treatment allocation by pre-defined sub-populations (i.e., sub-populations with and without prior ADHD treatments); white diamond represents the observed real-world practice.

Table

Treatments*	Drugs included
Amphetamine short-acting	Amphetamine aspartate/sulfate; dextroamphetamine saccharate/sulfate; methamphetamine hydrochloride; generic amphetamine aspartate/sulfate; generic dextroamphetamine saccharate/sulfate; generic methamphetamine hydrochloride
Amphetamine long-acting	Lisdexamfetamine dimesylate; amphetamine aspartate/sulfate long-acting; dextroamphetamine saccharate/sulfate long-acting; methamphetamine hydrochloride long-acting; generic amphetamine aspartate/sulfate long-acting; generic dextroamphetamine saccharate/sulfate long-acting; generic methamphetamine hydrochloride long-acting
Methylphenidate short-acting	Dexmethylphenidate hydrochloride; generic dexmethylphenidate hydrochloride; methylphenidate hydrochloride; generic methylphenidate hydrochloride
Methylphenidate long-acting	Osmotic-release oral system methylphenidate; methylphenidate hydrochloride long-acting; dexmethylphenidate hydrochloride long-acting; generic methylphenidate hydrochloride long-acting,
Non-stimulants	Guanfacine; clonidine; generic guanfacine short-acting; generic clonidine short-acting; guanfacine long-acting; clonidine long-acting; atomoxetine hydrochloride
Comorbidities	Conditions included
Any mental health condition	Oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, substance abuse, anxiety disorder, depression, adjustment disorder, bipolar disorder/mania, learning disability, tics
Neurological disorder	Epilepsy, cerebral degenerations, extrapyramidal disease and abnormal movement disorders, multiple sclerosis, cataplexy and narcolepsy, hypoxic-ischemic encephalopathy

*Anti-psychotics are not considered in this study because they can be used for other mental health conditions other than ADHD.